Encephalopathies - Childhood-onset Dystonia PDF

3688 Part XXV ◆ The Nervous System Childhood-onset dystonia DRUG-INDUCED DYSTONIAS...

3688 Part XXV ◆ The Nervous System Childhood-onset dystonia DRUG-INDUCED DYSTONIAS In the case of drug-induced dystonias, removal of the offending agent and treatment with intravenous diphenhydramine typically su$ce. For neuroleptic malignant syndrome, dantrolene may be indicated. As tar- Pilot dose of combination dive symptoms may not always respond to removal of the offending levodopa and carbidopa agent, dopamine depletors may be necessary Visit Elsevier Ebooks+ at eBooks.Health.Elsevier.com for Bibliography. Effective Not effective Further investigation Dopa-responsive dystonia Chapter 638 Continue dopaminergic therapy Disease-specific treatment Encephalopathies Elizabeth Barkoudah Generalized or segmental Focal Encephalopathy is a generalized disorder of cerebral function that may be acute or chronic, progressive or static. %e etiologies of the encephalopathies in children include infectious, toxic (carbon mon- Trihexyphenidyl Botulinum toxin oxide, drugs, lead), metabolic, genetic, and ischemic causes. Hypoxic- ischemic encephalopathy is discussed in Chapter 122.4. Gabapentin 638.1 Cerebral Palsy Clonidine, tetrabenazine, Elizabeth Barkoudah baclofen, benzodiazepines See also Chapters 56 and 637.4. Cerebral palsy (CP) is a complex and heterogeneous disorder denot- Severely impaired function in ing a group of permanent motor conditions that cause physical dis- activities of daily living, pain ability in human development, chie&y in the various areas of body movement. It can be defined as a central motor dysfunction affecting muscle tone, posture, and movement that is attributed to nonprogres- Consider indications for intrathecal sive disturbances in the developing fetal or infant brain. Despite being baclofen or pallidal stimulation described as a nonprogressive disorder (historically referred to as static encephalopathy by some), the clinical expression of brain injury or Fig. 637.9 Algorithm showing therapeutic approaches to the man- insult changes over time. %erefore the condition should be viewed as agement of childhood-onset dystonia. Pharmacologic agents should a dynamic disorder that evolves because of factors such as growth, ner- be used sparingly where possible. High doses and polypharmacy inevi- vous system maturation, and aging. tably arise when dystonia is severe enough to cause pain and interferes Several classification systems are used to describe CP, which with daily cares, sitting comfort, and sleep. As with intractable epilepsy, re&ects the complexity underlying the heterogeneity of cause, dis- consideration for functional neurosurgery should be considered when two or more drugs have failed to control dystonia. (From Lin JP. Advanc- tribution, type of motor involvement, and severity. Consideration of es in pharmacotherapies for movement disorders in children: current associated manifestations such as cognitive deficits, seizures, com- limitations and future progress. Curr Opin Pediatr. 2017;29:652–664, munication di$culties, visual impairment, and so on, as well as Fig. 6.) addressing the medical, surgical, and psychosocial needs requires a multidisciplinary approach. Oral medications are not the only options for treatment. Segmen- tal dystonia, such as torticollis, often responds well to botulinum toxin EPIDEMIOLOGY AND ETIOLOGY injections. Safe dosage restrictions limit the use of botulinum toxin in Cerebral palsy is the most common neuromotor disorder in child- generalized dystonia, but it may be used as a supplemental treatment hood, with an overall incidence of 2.6-2.9 cases per 1,000 live if symptoms in particular muscle groups are the most bothersome or births in the United States. Within developed countries, both cross- functionally impairing. sectional and cohort-based studies estimate prevalence of CP as Intrathecal baclofen delivered through an implantable constant- nearly 1-4 per 1,000 live births. In developing countries, available infusion pump may be helpful in some patients. It is often more effec- estimates of prevalence are similar. The estimated lifetime cost to tive in the lower extremities than the upper extremities. care for someone with CP in 2003, according to the Centers for Dis- Deep brain stimulation with leads implanted in the globus pallidus ease Control and Prevention (CDC), was $1 million. Adjusting for is most helpful for children with severe primary generalized dystonia. inflation, this is now $1.2 million per individual and will continue Deep brain stimulation may also be of benefit in children with second- to increase over time. ary dystonias, such as cerebral palsy, although the effect is not as robust. CP is caused by a broad group of developmental, genetic, metabolic, A combination of factors are thought to reduce the e$cacy in cerebral ischemic, infectious, and other etiologies that produce a common palsy, including a lack of normal neural substrate, reduced opportunity group of neurologic phenotypes. %us CP should be based on phe- for motor learning during critical developmental windows, and the fre- notype rather than etiology. %e prevalence of CP is higher for chil- quent presence of other neurologic impairments such as spasticity and dren born preterm or at a low birthweight, though this is in&uenced weakness. It should only be considered if a trial of two to three oral by sex, ethnicity, and socioeconomic status. %ere is a 30–40% greater agents has been unsuccessful.! prevalence in males. Prevalence is higher in low- and middle- versus ) D 4 4 4 4 4 @ A 0 C @ AE A ( ( E 2E @ C @ @ E. A @ @DA A @@ ( E AF @ C , A@ @ C 4  Chapter 638 ◆ Encephalopathies 3689 high-income communities. Rates of CP have only recently begun to In term births, causes historically have primarily been thought to be decrease in developed countries, though direct interpretation of trends by events during labor and delivery causing hypoxia. %e mechanisms is complicated by changing patterns of neonatal care and survivorhood. are predominately the result of cerebral ischemia and excitotoxicity. Although overall prevalence has &uctuated, the specific etiologies and %e cause can be obvious (i.e., placental abruption, meconium aspira- injury patterns have shifted over time given advances in perinatal and tion), though at other times the etiology can be di$cult to pinpoint. neonatal management. Risk factors can include eclampsia, hypercoagulability, and placental In addition to prematurity and birthweight, numerous other prena- pathology. For some, no predisposing clinical factors are identified. tal and perinatal risk factors have been reported, though for many of Hypoxic-ischemic encephalopathy (HIE) may be decreasing as an these, a causal relationship has not been established. %ese risk factors apparent cause of CP in developed countries. %erapeutic hypothermia include antenatal infection (chorioamnionitis, urinary tract infection), may reduce the risk of CP in term patients with HIE. multiple pregnancy, and neonatal infection. Infertility treatments are %ere are several causes of acquired CP. %e most common cause in also associated with a higher rate of CP, probably because these treat- this category is perinatal stroke, which can be ischemic, hemorrhagic, ments are often associated with multiple pregnancies. CP is most often or thromboembolic in nature. %e second most common cause is men- multifactorial, and multiple risk factors coexist. ingitis or encephalitis during infancy. Kernicterus is a rare cause of %e cerebral disruption associated with CP can occur prenatally, CP in developed countries, though cases (particularly in very preterm perinatally, or postnatally in the first 2 years of life given that brain infants) persist. development is ongoing during this critical period. Congenital CP (due Cryptogenic CP traditionally refers to an individual in which no to cerebral injury/maldevelopment before or during birth) accounts clear perinatal etiology has been identified and accounts for ∼30% of for 85–90% of total cases, whereas acquired CP (due to cerebral injury cases. Chromosomal copy number variants and single gene disorders after 1 month of life) is responsible for the remaining cases. have been identified in ∼30% of patients with CP. Monogenic genetic One can also consider different etiologies based on premature ver- variants have been identified in ∼30% of cases who met diagnostic cri- sus term births. %e major lesions that contribute to CP in preterm teria for CP. A wide range of genes have been implicated in CP phe- infants are intracerebral hemorrhage and periventricular leuko- notypes, though a few are relatively more frequently seen including malacia (PVL). Although the incidence of intracerebral hemorrhage TUBA1A, TUBB4A, COL4A1, SPAST, CTNNB1, GNAO1, STXBP1, has declined significantly, PVL remains a major problem. %e inci- and KIF1A. Factors associated with exome sequencing–identified gene dence of cystic PVL caused by a more diffuse injury pattern is being variants include patients without a perinatal risk factor, those with a replaced by focal necrosis. PVL re&ects the enhanced vulnerability positive family history, and patients with intellectual disability, epi- of immature oligodendroglia in premature infants to oxidative stress lepsy, or autism spectrum disorders.! caused by ischemia or infectious/in&ammatory insults. White matter abnormalities (loss of volume of periventricular white matter, extent CLINICAL MANIFESTATIONS of cystic changes, ventricular dilation, thinning of the corpus callo- %ere are several classification systems to describe CP, a re&ection of sum) present on MRI at 40 weeks of gestational age in former preterm the complexity underlying the heterogeneity of cause, distribution, infants are a predictor of later CP. MRI with diffusion tensor imaging type of motor involvement, and severity (Table 638.1). Classification is being used to map white matter tracts more precisely in patients aids in understanding cause, coordinating care, monitoring comor- with spastic diplegia, and this technique has shown that thalamocor- bidities, treatment offerings and their prognosis, and long-term out- tical sensory pathways are often injured as severely as motor cortico- comes. One such classification system starts by determining the type of spinal pathways (Fig. 638.1). motor involvement: spastic or extrapyramidal. Spastic CP can then be Lateral Posterior thalamic radiation Fibers penetrating the posterior limb of internal capsule Fig. 638.1 Diffusion tensor image AP of white matter pathways in the brains of two patients with spastic diplegia on the right compared with a normal child on the far left. Yellow fibers are corticospinal pathways projected from the motor cerebral cortex at the top downward into the brainstem, whereas red fibers are thalamocortical sensory Left fibers projected from the thalamus superior upward to the cortex. In children with oblique spastic diplegia, both the corticospi- nal and thalamocortical pathways are reduced in size but the ascending thalamocortical pathways are more affected. (From Nagae LM, Hoon AH Jr, Stashinko E, et al. Diffusion tensor imaging in children with periventricular leukomalacia: variability of injuries to white matter tracts. AJNR Am J Neuro- radiol. 2007;28:1213–1222.) ) D 4 4 4 4 4 @ A 0 C @ AE A ( ( E 2E @ C @ @ E. A @ @DA A @@ ( E AF @ C , A@ @ C 4 3690 Part XXV ◆ The Nervous System Table 638.1 Classification of Cerebral Palsy and Major Causes MOTOR SYNDROME (APPROX % OF CP) NEUROPATHOLOGY/MRI MAJOR CAUSES Spastic diplegia (35%) Periventricular leukomalacia Prematurity Periventricular cysts or scars in white matter, Ischemia enlargement of ventricles, squared-off Infection posterior ventricles Endocrine/metabolic (e.g., thyroid) Spastic quadriplegia (20%) Periventricular leukomalacia Ischemia, infection Multicystic encephalomalacia Endocrine/metabolic, genetic/developmental Cortical malformations Hemiplegia (25%) Stroke: in utero or neonatal Thrombophilic disorders Focal infarct or cortical, subcortical damage Infection Cortical malformations Genetic/developmental Periventricular hemorrhagic infarction Extrapyramidal (athetoid, dyskinetic) (15%) Asphyxia: symmetric scars in putamen and Hypoxia thalamus Kernicterus Kernicterus: scars in globus pallidus, Mitochondrial hippocampus Genetic/metabolic Mitochondrial: scarring of globus pallidus, caudate, putamen, brainstem No lesions: ? dopa-responsive dystonia further truncated topographically (Fig. 638.2), whereas extrapyrami- oligodendroglia between 20 and 34 weeks of gestation, hence seen in dal is further categorized based on the type of involuntary movement those born prematurely. %e first clinical indication of spastic diple- seen. In extrapyramidal CP, the brain injury or insult spares the pyra- gia is often noted when an affected infant begins to crawl. %e child midal tracts that cause spasticity resulting in disorders of movement, uses the arms in a normal reciprocal fashion but tends to drag the legs coordination, and balance. Clinically, these patients exhibit dystonia behind more as a rudder (commando crawl) rather than using the nor- and/or choreoathetosis (collectively referred to as dyskinetic) or ataxia mal four-limbed crawling movement. If the spasticity is severe, appli- associated with lesions in the cerebellum or its connections. Spastic CP cation of a diaper is di$cult because of the excessive adduction of the accounts for 80% of cases, whereas extrapyramidal makes up 20% of hips. Examination of the child reveals symmetric spasticity in the legs cases (15% dyskinetic and 5% ataxic). with brisk re&exes, ankle clonus, and a bilateral Babinski sign. When Historically, CP has been classified as mild, moderate, and severe the child is suspended by the axillae, an extended scissoring posture without specified criteria for each group and primarily used for diag- of the lower extremities is maintained. Walking can be significantly nostic purposes. %e Gross Motor Function Classification System delayed, the feet are held in a position of equinovarus, and the child (GMFCS) was developed to categorize CP based on abilities and limita- walks on tiptoes. Severe spastic diplegia is characterized by disuse atro- tions in motor functioning. Goals included improved communication phy, impaired growth of the lower extremities, and disproportionate for treatment decisions, research into treatment outcomes, improved growth with normal development of the upper torso. understanding and communication of the development of a child with Spastic quadriplegia is the most severe form of CP because of CP, and anticipated future ambulatory needs. %e emphasis is on usual marked motor impairment of all extremities and the high association rather than best motor performance in a variety of settings: home, with other comorbidities, including intellectual disabilities, seizure school, and community. disorders, communication and visual impairment, and feeding di$- Spastic hemiplegia has decreased spontaneous movements on the culties. Swallowing di$culties are common as a result of supranuclear affected side and shows hand (handedness) preference at a very early bulbar palsies, often leading to aspiration pneumonia and growth fail- age. %e arm is often more involved than the leg, and di$culty in hand ure. Neurologic examination shows increased tone and spasticity in manipulation is evident by 1 year of age. Walking is usually delayed all extremities, decreased spontaneous movements, brisk re&exes, and until 18-24 months, and a circumductive gait is apparent. Examina- plantar extensor responses. Flexion contractures of the knees, elbows, tion of the extremities may show growth arrest leading to shortened and wrists are often present by late childhood. Children with spastic limbs and decreased muscle bulk on the affected side. Spasticity refers quadriparesis can also have extrapyramidal findings given the diffuse to the quality of increased muscle tone, which increases with the speed involvement of the brain injury. of passive muscle stretching and is greatest in antigravity muscles. It is Extrapyramidal CP can be divided into the two main types of apparent in the affected extremities, particularly at the ankle, causing involuntary movement seen: ataxia and dyskinesias. In this type of CP, an equinovarus deformity of the foot. An affected child often walks injury is typically to the subcortical areas, which are centers for coor- on tiptoe (toe-walking) because of the increased tone in the antigrav- dination in movement and balance. Injury may not produce weakness, ity gastrocnemius muscles and tight contracted Achilles tendon; the but rather the inability to voluntarily control movements. %is type is affected upper extremity assumes a &exed posture when the child runs. less common than spastic CP and makes up approximately 15–20% of Ankle clonus and a Babinski sign may be present, the deep tendon patients with CP. re&exes are increased, and weakness of the hand and foot dorsi&exors Ataxic CP is the rarest form whose clinical picture is variable rang- is evident. Di$culty in selective motor control is also present. ing from hypotonia to mild spasticity in addition to incoordination Spastic monoplegia is when only one limb is affected and may depending on the other systems involved. Walking gait is often very not be as obvious as other types of CP. Depending on which limb is wide and sometimes irregular. Control of eye movements and depth affected, the child’s motor disability ranges from challenges with either perception can be impaired. Often, fine motor skills requiring coor- fine or gross motor skills. A monoplegia that affects the arm may result dination of the eyes and hands, such as writing, are di$cult. Other in challenges with bimanual tasks, whereas when the legs are involved, causes of ataxia in infancy and childhood, including hydrocephalus, toe walking may be seen. neoplasms, and degenerative disorders, should be ruled out before CP Spastic diplegia is bilateral spasticity of the legs that is greater than is diagnosed (see Chapter 637.1). in the arms. Spastic diplegia is strongly associated with injury to the Dyskinetic CP is further divided into two groups: athetoid and immature white matter during the vulnerable period of immature dystonic. Athetoid CP includes cases with involuntary movement, ) D 4 4 4 4 4 @ A 0 C @ AE A ( ( E 2E @ C @ @ E. A @ @DA A @@ ( E AF @ C , A@ @ C 4  Chapter 638 ◆ Encephalopathies 3691 Unilateral Cerebral Palsy Nearly all individuals with CP will have one or more medical, neu- rologic, or psychiatric comorbidities. Neuropsychiatric comorbidities that occur at higher rates with CP include intellectual disability, anxi- ety, depression, and attention-deficit/hyperactivity disorder (ADHD) compared with the general population. Other associated comorbidi- ties are common and include chronic pain, sleep di$culties, urinary dysfunction, decreased bone health, sialorrhea, respiratory disorders, feeding and growth challenges, gastrointestinal disorders includ- ing constipation and dysmotility, speech/communication di$culties, visual impairment, and hearing loss.! DIAGNOSIS CP is a clinical diagnosis that considers elements from the history, physical examination, and ancillary testing including neuroimaging. %e history should focus on whether there was perinatal or postnatal injury to the brain, what factors led to this injury, and contributory pregnancy factors. Another important factor is the developmental tra- Monoplegia Hemiplegia jectory. It is important to quantify rates of development in the vari- ous domains and whether that trajectory has been one of continued acquisition of skills, plateauing, or regression. %is—especially no loss Bilateral Cerebral Palsy of acquired milestones (regression)—helps preclude a progressive dis- order of the central nervous system (CNS), including degenerative dis- eases, metabolic disorders, spinal cord tumor, or muscular dystrophy. Multiple components to the physical examination are necessary to char- acterize abnormalities of tone, re&exes, movements, posture, and balance that may be consistent with the diagnosis of CP. %e physical examina- tion should focus on the following features: presence of any limb deformi- ties, curvature of the spine, range of motion of joints, muscle tone, muscle strength, re&exes, presence of any movement disorders, and gait. An MRI scan of the brain is indicated to determine the location and extent of structural lesions or associated congenital malformations; an MRI scan of the spinal cord is indicated if there is any question about spinal cord pathology. An MRI with abnormalities consistent with CP supports the diagnosis and increases the level of certainty, but the diagnosis remains a clinical one. An early diagnosis of CP is desirable to initiate appropriate services and therapies and to provide a definitive diagnosis for families. Additional studies may include tests of hearing and visual function. Genetic Diplegia Triplegia Quadriplegia evaluation should be considered in patients with congenital malformations, Fig 638.2 Topographical description in spastic cerebral palsy. Spastic evidence of metabolic disorders (e.g., amino acids, organic acids, MR spectros- cerebral palsy accounts for 70–80% of cases and is caused by an in- copy), clinical features atypical of CP, or when there are no perinatal risk factors jury of the pyramidal tracts affecting voluntary movement. Monoplegia especially in term infants (Fig. 638.3, Tables 638.2 and 638.3). and hemiplegia affect one side of the body; in monoplegia one limb %e differential diagnosis must include disorders that may mimic the is affected, whereas in hemiplegia both the arm and leg on one side various types of CP (see Fig. 638.3). %ese may include the hereditary are affected. Hemiplegia can be asymmetric, affecting the arm or leg spastic diplegias (Table 638.4), monoamine transmitter disorders such as greater than the other extremity. Diplegia, triplegia, and quadriplegia affect both sides of the body. In diplegia, the predominant picture is in- dihydroxyphenylalanine (DOPA)-responsive dystonia (Segawa disease) volvement of the lower extremities. However, the arms can be affected (Table 638.5 and Fig. 638.4), and many treatable inborn errors of metab- though not to the same degree. In triplegia, both lower extremities and olism, including disorders of amino acids, creatine, fatty acid oxidation, one arm are affected. A common picture is diplegia from periventricular lysosomes, mitochondria, organic acids, and vitamin cofactors.! leukomalacia and hemiplegia from an interventricular hemorrhage. This results in one lower extremity being more severely affected because of TREATMENT a dual mechanism of injury. In quadriplegia, all extremities are involved. %e treatment strategy for CP is best developed in a multidisciplinary (From Graham HK, Rosenbaum P, Paneth N, et al. Cerebral palsy. Nat patient-centered setting, where medical interventions are embedded in Rev Dis Primers. 2016;2:15082, Fig. 2.) a rehabilitation context considering the patient’s individual goals (see Chapter 752). %e overarching goal for patients with CP is to maximize especially in the arms, legs, and hands. With the current management functioning by improved biomechanics resulting from abnormal tone, of Rh and ABO incompatibility, the incidence of CP characterized by musculoskeletal deformities, and muscle weakness. Other goals outside athetosis has markedly decreased (see Chapter 637). Athetoid CP is of those related to the neuromotor component can be equally important often caused by kernicterus secondary to high levels of bilirubin, and when they pertain to quality of life, comfort, and social stigmatization. in this case the MRI scan shows lesions in the globus pallidus bilater- Clear communication and coordination among the multidisciplinary ally, or it may be normal. Cases are still seen as a result of HIE as well. team (physiatry, orthopedic, neurology/neurodevelopmentalists, neu- %e affected infant is initially hypotonic, but a tendency toward arch- rosurgery) as well as physical and occupational therapy, speech pathol- ing and opisthotonus (dystonia) is noted, and obligatory tonic neck ogy, social work, primary care physicians, developmental pediatricians, re&exes are present. %ese primitive motor patterns preclude orderly and educators maximize the chances of success. motor development such as reaching, rolling, and sitting. Dystonic CP Parents should be taught how to work with their child in daily activi- encompasses cases that affect the trunk muscles more than the limbs ties such as feeding, carrying, dressing, bathing, and playing in ways that and results in a fixed, twisted posture. Toward the end of the first year, reduce the effects of abnormal muscle tone. Families and children also repetitive, involuntary movements become more consistent with the need to be instructed in the performance of a series of exercises designed full-blown picture of dystonic CP. Dystonia in CP presents as hyperto- to promote developmental progress, prevent long-term complications nia, involuntary postures and movements, or a combination. such as the development of contractures, preserve range of motion, ) D 4 4 4 4 4 @ A 0 C @ AE A ( ( E 2E @ C @ @ E. A @ @DA A @@ ( E AF @ C , A@ @ C 4 3692 Part XXV ◆ The Nervous System History/exam inconsistent with CP due to perinatal brain injury Abnormal Directed genetic testing MRI brain +/– spinal cord based on specific findingsa Normal/non-specific Initial biochemical and genetic studies to consider Infantile developmental delay, Spasticity Dystonia/chorea Ataxia mixed motor syndrome Serum TSH Serum ammonia Serum TSH Serum AFP Serum uric acid Serum lactate Serum uric acid Serum lactate, pyruvate Serum amino acids Serum amino acids Serum AFP Serum biotinidase activity Serum lactate, pyruvate (including arginine, serine) Serum lactate, pyruvate Urine organic acids Serum acylcarnitines Urine organic acids Serum acylcarnitines Mitochondrial genetic Serum biotinidase activity Serum biotinidase activity Urine organic acids analysis, CoQ10 level Urine organic acids Urine purines, pyrimidines SNP-CGH microarray* CSF studiesb Genetic testing for HSP Urine creatine, GAA SNP-CGH microarray* SNP-CGH microarray* CSF studiesb Genetic testing for NKX2.1 SNP-CGH microarray* Consider multi-gene panel or WES based on phenotype, clinical and family history Fig. 638.3 Genetic mimics of cerebral palsy. Algorithm showing the general diagnostic approach to the patient with an infantile-onset, appar- ently nonprogressive motor disorder. Studies are grouped by predominant clinical presentation; it may be appropriate to consider investigations from more than one group depending on the specific clinical context. *In many situations WES has replaced microarray testing. aSee examples in Tables 638.2 and 638.3 bCSF studies: glucose (+ serum glucose), lactate, pyruvate, neurotransmitter metabolites (biogenic amines + GABA), pterins, 5-methyltetrahydrofolate; HSP, hereditary spastic paraplegia. (From Pearson TS, Pons R, Ghaoui R, Sue CM. Genetic mimics of cerebral palsy. Mov Disord. 2019;34:625–636, Fig. 1, p. 627.) Table 638.2 Clinical Features That Should Prompt Table 638.3 Brain MRI Findings Suggestive of Selected Evaluation for Genetic and Metabolic Genetic CP Mimics Conditions in a Patient Presenting with Symptoms of CP FINDING SELECTED CONDITIONS Hypomyelination PLP1-related dysmyelinating Absent history of any perinatal risk factor for brain injury disorders Family history of sibling with similar neurologic symptoms H-ABC (TUBB4A variant) Motor symptom onset after an initial period of normal development AGS (may also have basal Developmental regression ganglia and WM calcification) Progressive neurologic symptoms GM1 gangliosidosis Paroxysmal motor symptoms or marked fluctuation of motor symptoms Demyelination Krabbe disease Clinical exacerbation in the setting of a catabolic state (e.g., febrile Metachromatic leukodystrophy illness) Isolated generalized hypotonia Thin corpus callosum HSP (i.e., SPG4, SPG11, SPG15, Prominent ataxia and others) Signs of peripheral neuromuscular disease (reduced or absent Globus pallidus lesions T2-hypointense: NBIA (SN also reflexes, sensory loss) involved in BPAN, MPAN), Eye movement abnormalities (e.g., oculogyria, oculomotor apraxia, fucosidosis or paroxysmal saccadic eye-head movements) T2-hyperintense: MMA, PDH From Pearson TS, Pons R, Ghaoui R, et al. Genetic mimics of cerebral palsy. Mov deficiency, creatine deficiency Disord. 2019;34:625–636, Table. 1, p. 628. syndromes Focal atrophy or hypoplasia Glutaric aciduria type 1 (frontotemporal) and strengthen weak muscles. %erapists help children to achieve their H-ABC (cerebellum ± putamen) full potential and often recommend further evaluations and adaptive Joubert syndrome (cerebellum) equipment. AGS, Aicardi-Goutières syndrome; BPAN, beta-propeller protein–associated Rehabilitative strategies include orthotics, casting, and physiother- neurodegeneration; H-ABC, hypomyelination with atrophy of the basal ganglia apy (see Chapter 752). Adaptive equipment can help individuals with CP and cerebellum; HSP, hereditary spastic paraplegia; MMA, methylmalonic aciduria; achieve a greater level of independence and autonomy. Equipment such MPAN, mitochondrial membrane protein-associated neurodegeneration; NBIA, as braces, wheelchairs, and walkers can significantly improve mobility neurodegeneration with brain iron accumulation; PDH, pyruvate dehydrogenase; WM, white matter. and increase self-confidence. Orthotics are devices that are used to help From Pearson TS, Pons R, Ghaoui R, et al. Genetic mimics of cerebral palsy. Mov prevent foot and ankle deformities, improve stability during walking, and Disord. 2019;34:625–636, Table 2, p. 628. ) D 4 4 4 4 4 @ A 0 C @ AE A ( ( E 2E @ C @ @ E. A @ @DA A @@ ( E AF @ C , A@ @ C 4  Chapter 638 ◆ Encephalopathies 3693 Table 638.4 Clinical and Neuroimaging Findings in Hereditary Spastic Paraplegias (HSP) with Pediatric Onset* CHILDHOOD NEUROIMAGING HSP FORM HSP TYPE INHERITANCE GENE ONSET DISEASE CHARACTERISTICS† FINDINGS (BRAIN) Pure SPG3A AD ATL1 +++ None Normal Pure SPG4 AD SPAST ++ None Leukoencephalopathy, thin corpus callosum Pure SPG6 AD NIPA1 + None Normal Pure SPG10 AD KIF5A +++ Neuropathy Normal Pure SPG12 AD RTN2 +++ None Normal Pure SPG31 AD REEP1 ++ None Normal Complicated SPG1 X-linked L1CAM ++ Intellectual disability, adducted Thin corpus callosum thumb Complicated SPG2 X-linked PLP1 +++ Intellectual disability, epilepsy Normal Complicated SPG7 AR SPG7 + Optic atrophy, neuropathy, Cerebellar atrophy cerebellar ataxia Complicated SPG11 AR KIAA1840 +++ Intellectual disability, neuropathy Leukoencephalopathy, thin corpus callosum Complicated SPG15 AR ZFYVE26 +++ Intellectual disability, retinopathy, Leukoencephalopathy, cerebellar ataxia thin corpus callosum Complicated SPG17 AR BSCL2 + Neuropathy Normal *Onset before 18 yr of age. †Other than the classic HSP symptoms, including spastic paraparesis, atrophy of the distal lower extremities, and neurogenic bladder dysfunction. AD, autosomal dominant; AR., autosomal recessive; +, occasional; ++, common; +++, characteristic. From Lee RW, Poretti A, Cohen JS, et al. A diagnostic approach for cerebral palsy in the genomic era. Neurol Med. 2014;16:821–844, Table 5, p. 832. Table 638.5 Clinical Features of the Monoamine Neurotransmitter Disorders MOTOR AND EXTRAPYRAMIDAL EXTRAPYRAMIDAL PYRAMIDAL ENZYME AGE AT COGNITIVE HYPERKINETIC HYPOKINETIC TRACT AUTONOMIC NEUROPSYCHIATRIC DEFICIENCY PRESENTATION DELAY FEATURES FEATURES FEATURES EPILEPSY FEATURES FEATURES AD Childhood (but Not Yes Yes No No No Yes GTPCH-D can occur at any common age) SR-D Infancy In most Yes Yes Yes Yes Yes Yes AR Infancy Yes Yes Yes Yes Yes Yes Yes GTPCH-D PTPS-D Infancy to In most Yes Yes Yes Yes Yes Yes childhood DHPR-D Infancy to Yes Yes Yes Yes Yes Yes Yes childhood PCD-D Infancy No No No No No No No TH-D Infancy to early In most Yes Yes Yes Yes Yes No childhood AADC-D Mainly infancy Yes Yes Yes Yes Yes Yes Yes (but can occur at any age) PLP-DE Infancy to early In most Yes Yes Yes Yes Yes Yes childhood DTDS Infancy Yes Yes Yes Yes, in older No Yes No children AD GTPCH-D, autosomal dominant GTP cyclohydrolase deficiency; SR-D, D-Serine; AR GTPCH-D, autosomal recessive GTP cyclohydrolase deficiency; PTPS-D, 6-pyruvoyl tetrahydropterin synthase deficiency; DHPR-D, dihydropteridine reductase deficiency; PCD-D, pterin-4α carbinolamine dehydrase deficiency; TH-D, tyrosine hydroxylase deficiency; AADC-D, aromatic l-amino acid decarboxylase deficiency; PLP-DE, pyridoxal 5 phosphate dependent enzymes; DTDS, dopamine transporter deficiency syndrome. From Kurian MA, Gissen P, Smith M, et al. The monoamine neurotransmitter disorders: an expanding range of neurological syndromes. Lancet Neurol. 2011;10:721–731, Table, p. 722. ) D 4 4 4 4 4 @ A 0 C @ AE A ( ( E 2E @ C @ @ E. A @ @DA A @@ ( E AF @ C , A@ @ C 4 3694 Part XXV ◆ The Nervous System The monoamine neurotransmitter disorders Primary monoamine Secondary monoamine neurotransmitter Monoamine neurotransmitter neurotransmitter disorders defects in neurologic disorders disorders of unknown origin Cofactor deficiency Enzyme deficiency Defective monoamine Mitochondrial diseases Disorders of selective serotonin transport Rett syndrome deficiency Epileptic encephalopathies DNRD Pontocerebellar hypoplasia Idiopathic focal dystonia Vitamin B6 BH4 deficiency Perinatal asphyxia PKD TH-D DTDS deficiency AADC-D Disorders of folate metabolism Phenylketonuria Lesch-Nyhan disease Opsoclonus-myoclonus Phenylalanine Phenylalanine level normal level abnormal Leukodystrophies Neuropsychiatric disorders Dystonic disorders Neuromuscular disorders PLP-DE AD GTPCH-D AR GTPCH-D Spontaneous periodic hypothermia P-DE SR-D PTPS-D and hyperhidrosis DHPR-D Pelizeaus-Merzbacher HIE PKAN Cerebral palsy Autistic spectrum disorder Non-specific developmental delay Fig. 638.4 Classification of the monoamine neurotransmitter disorders. BH4, Tetrahydrobiopterin; TH-D, tyrosine hydroxylase deficiency; AADC- D, aromatic L-amino acid decarboxylase deficiency; DTDS, dopamine transporter deficiency syndrome; PLP-DE, pyridoxal-phosphate–dependent epilepsy; P-DE, pyridoxine-dependent epilepsy; AD GTPCH-D, autosomal dominant GTP cyclohydrolase 1 deficiency; SR-D, sepiapterin reductase deficiency; AR GTPCH-D, autosomal recessive GTP cyclohydrolase 1 deficiency; PTPS-D, 6-pyruvoyltetrahydropterin synthase deficiency; DHPR-D, dihydropteridine reductase deficiency; HIE, hypoxic-ischemic encephalopathy; PKAN, pantothenate kinase associated neurodegeneration; DNRD, dopa-nonresponsive dystonia; PKD, paroxysmal kinesigenic dyskinesia. (From Kurian MA, Gissen P, Smith M, et al. The monoamine neurotransmitter disorders: an expanding range of neurological syndromes. Lancet Neurol. 2011;10:721–731, Fig. 1.) sometimes relieve pain. Additional equipment needs address activities of weakness, or gastrointestinal (GI) symptoms. Baclofen is delivered daily living such as bathing and hygiene, communication, and driving. with an implanted pump in children with severe spasticity; it is useful Pharmacotherapy is often the first-line approach used to manage because it delivers the drug directly around the spinal cord, where it the various tone abnormalities seen in CP and includes both enteral reduces neurotransmission of afferent nerve fibers. Direct delivery to options and targeted injections. Systemic medications are often cho- the spinal cord overcomes the problem of CNS side effects caused by sen for more widespread management of spasticity and dyskinesias. the large oral doses needed to penetrate the blood-brain barrier. ITB Although baclofen is routinely favored, other antispasticity medica- may reduce dystonia with evidence for benefit with higher catheter tions such as tizanidine, dantrolene, and benzodiazepines are also placement. available. Second-line medications such as clonidine or gabapentin %e main goal of SDR is to improve the gait or functioning in those may provide dual benefit for both tone management and other neuro- that function at GMFCS I-III with good selective motor control and logic associations, including sleep disruption, dysautonomia, pain, and minimal weakness. However, SDR is being looked at for manage- neuroirritability. Medications used to treat dystonia include enteral ment of tone, minimizing pain, and ease of caregiving in patients baclofen, benzodiazepines, trihexyphenidyl, clonidine, dantrolene, functioning on a GMFCS IV-V level. Because SDR is an irreversible levodopamine, and gabapentin, but practice varies widely. Tetrabena- treatment for spasticity, optimal selection of ideal candidates from zine can be useful for hyperkinetic movement disorders, including ath- a multidisciplinary approach is necessary to avoid short- and long- etosis or chorea. term complications. SDR’s spasticity benefits are caused by a partial %e management of focal/segmental spasticity or dystonia includes sensory deafferentation of the spinal cord. %is is achieved by resec- chemodenervation agents that target these specific locations. Tar- tion of dorsal nerve rootlets based on abnormal motor responses to geted injections are often used in combination with systemic medica- electrical stimulation (Fig. 638.5). %e total number of nerve root- tions to augment tone management in specific areas that are more lets resected ranges from 25% to 40%, though in some institutions problematic. Examples include botulinum toxin A (BoNT-A), phe- it exceeds >40%. Combining both ventral and dorsal rhizotomies nol, and ethyl alcohol. Targeted injections combined with rehabilita- can help manage both spasticity and dystonia. SDR manages lower tive therapies can allow for improved motor functioning and delay extremity tone equally as the ITB pump, may provide more upper- or avoid orthopedic surgery; these injections require repeat adminis- extremity tone control compared with the ITB pump, and improves tration. Typically repeat injections are performed every 4-6 months, bladder function. primarily to avoid the development of resistance; 3 months may be DBS can be considered if there is severe hypertonia with com- necessary. Injections into salivary glands may also help reduce the bined spasticity and dystonia. DBS is a neurosurgical procedure that severity of drooling if it is not adequately treated with anticholinergic evolved from the recognition that pallidotomies and thalamotomies agents. could help patients with medically refractory dystonia. It involves Neurosurgical options include intrathecal baclofen (ITB), selective the introduction of stimulating electrodes in areas of the brain such dorsal rhizotomy (SDR), and deep brain stimulation (DBS). ITB can be as the globus pallidus and the subthalamic nucleus, which are con- considered in patients whose spasticity is not adequately treated with nected to an extracranial pulse generator (see Chapter 637). After enteral baclofen or who are experiencing side effects such as sedation, the surgical procedure, the beneficial effects are not immediately ) D 4 4 4 4 4 @ A 0 C @ AE A ( ( E 2E @ C @ @ E. A @ @DA A @@ ( E AF @ C , A@ @ C 4  Chapter 638 ◆ Encephalopathies 3695 Encephalopathy–strokes, seizures, developmental delay and regression Ptosis, PEO, optic atrophy, pigmentary SNHL retinopathy Cardiomyopathy, conduction defects A Liver failure Diabetes, pancreatic exocrine insufficiency Enteropathy Renal tubulopathy Myopathy Anemia B Fig. 638.5 Schematic of the technique of selective dorsal rhizotomy. Peripheral neuropathy A, After laminectomy, the dura is opened and the dorsal spinal rootlets are exposed. The rootlets are stimulated so that abnormal rootlet activ- Fig. 638.6 Clinical features of mitochondrial encephalomyopathies. ity can be identified. B, A proportion of rootlets is transected. (From PEO, progressive external ophthalmoplegia; SNHL, sensorineural hear- Koman LA, Smith BP, Shilt JS. Cerebral palsy. Lancet. 004;363:1619– ing loss. (Adapted from Rahman S. Mitochondrial disease in children. 1631. Reproduced with permission from Wake Forest University Ortho- J Intern Med. 2020;287:609–633.) paedic Press.) clusters, and lipoic acid. Aberrant mitochondrial function most com- visible, often taking several months. The procedure is associated monly involves disturbed energy generation via the OXPHOS system, with perioperative risks as well as infection and hardware compli- but other mechanisms include oxidative stress mediated by increased cations. Therefore patient selection and consideration of the appro- production of reactive oxygen species (ROS), alterations of other meta- priate target for stimulation for DBS are key. Most agree that the bolic processes within the mitochondria (such as pyruvate dehydroge- presence of spasticity, contractures/deformities, and myelopathy nase, the Krebs cycle, vitamin metabolism and transport, and cofactor are poor predictors of response and that neurosurgical expertise, biosynthesis) and of the mitochondrial lipid membranes, protein qual- anatomic factors, and severity/time of dystonic symptoms may ity control, import system, and organelle dynamics (disturbed fission influence response. and fusion). Orthopedic interventions address musculoskeletal pathol- Mitochondria are unique among cellular organelles in that they ogy, including fixed muscle contractures, torsion of long bones, contain their own genome: the maternally inherited circular mito- hip displacement, and spine deformities. Several surgical meth- chondrial DNA (mtDNA) molecule comprising 16,569 base pairs in ods exist for lengthening the muscle- tendon units for contraction humans encoding 37 genes: 13 protein-coding genes, 22 transfer RNAs management, though these are rarely necessary before 6 years of (tRNAs), and 2 ribosomal RNAs (rRNAs). %e mitochondrial genome age. Before this, prevention of contracture development is key is present in multiple copies within each mitochondrion, and there and often is a combination of tone management, bracing, and are hundreds to thousands of mtDNA molecules per cell. mtDNA stretching exercises. Femoral and tibial torsion occur, respectively, gene variants may be heteroplasmic (only a percentage of the mtDNA because of failure of remodeling fetal anteversion and mostly as is mutated) or homoplasmic (100% of the mtDNA is mutated). Pri- a response to abnormal biomechanical forces during walking. mary mitochondrial disease may be caused by maternally inherited Derotational osteotomies are ideally performed between 6 and or sporadic variants affecting the mtDNA or by recessive, dominant, 12 years of age. With increasing GMFCS level comes increased X-linked, or de novo variants in nearly 400 nuclear genes involved in risk of developing hip displacement and neuromuscular scoliosis. mitochondrial function and structure. Monitoring and prevention strategies are paramount, as both hip Mitochondrial disorders, especially those presenting in childhood, displacement and scoliosis may progress with age. Conservative have a predilection for high-energy-consuming organs: the brain, skel- treatment and surgical approaches can be challenging when bal- etal muscle, eyes, ears, heart, kidneys, and liver. Neurologic features of ancing the complexity of these surgical interventions and outcome primary mitochondrial disease in childhood include hypotonia, dysto- goals defined presurgically. nia, spasticity, ptosis, progressive external ophthalmoplegia (PEO), sei- zures, and ataxia. Multisystem features that may be observed in children Visit Elsevier eBooks+ at eBooks.Health.Elsevier.com for Bibliography. with mitochondrial disease are illustrated in Figure 638.6. Some mito- chondrial syndromes with characteristic constellations of symptoms and signs were recognized many decades before their genetic basis was understood; several of these syndromes are summarized in Table 638.6. 638.2 Mitochondrial Encephalomyopathies Mitochondrial encephalomyopathies can be considered according Shamima Rahman to age at onset of symptoms. In early infancy the most frequent pre- sentations include Leigh syndrome, the mtDNA depletion syndromes Mitochondrial encephalomyopathies are complex neurologic disor- (MDDS), disorders of coenzyme Q10 (CoQ10) biosynthesis, and revers- ders caused by disturbed mitochondrial function. Mitochondria are ible infantile respiratory chain disease (RIRCD). Clinical syndromes dynamic cellular organelles with multitudinous roles, most notably observed later in childhood include Kearns-Sayre syndrome (KSS), energy generation via oxidative phosphorylation (OXPHOS), but mitochondrial encephalomyopathy with lactic acidosis and stroke- other mitochondrial functions include intermediary metabolism (the like episodes (MELAS), myoclonic epilepsy with ragged red fibers Krebs cycle, fatty acid beta oxidation, and part of the urea cycle are (MERRF), and neurogenic muscle weakness, ataxia, and retinitis pig- housed in the mitochondrion), calcium homeostasis, intracellular sig- mentosa (NARP). However, many children presenting with mitochon- naling, apoptosis, and biosynthesis of coenzyme Q10, heme, iron-sulfur drial disease have overlapping features not specific to an individual ) D 4 4 4 4 4 @ A 0 C @ AE A ( ( E 2E @ C @ @ E. A @ @DA A @@ ( E AF @ C , A@ @ C 4 3696 Part XXV ◆ The Nervous System Table 638.6 Clinical Manifestations of Syndromic Mitochondrial Encephalomyopathies TISSUE SYMPTOMS/SIGNS LSS KSS MELAS MERRF NARP LHON CNS Regression + + + + Seizures ± + + Ataxia ± + + + + Cortical blindness ± + Deafness ± + + Migraine + Hemiparesis + Myoclonus + + Movement disorder + + + ± Nerve Peripheral neuropathy ± + + + + Muscle Ophthalmoplegia ± + Weakness + + + + + RRF on muscle biopsy ± + + + Ptosis ± + Eye Pigmentary ± + + retinopathy Optic atrophy + + + Heart Conduction block + ± Cardiomyopathy ± + Lactic acidosis + + + + + Endocrine Diabetes mellitus + + Short stature + + + + Kidney Tubulopathy ± + + + KSS, Kearns-Sayre syndrome; LHON, Leber hereditary optic neuropathy; MELAS, mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes; MERRF, myoclonic epilepsy with ragged red fibers; NARP, neuropathy, ataxia, and retinitis pigmentosa; RRF, ragged red fibers. Courtesy Prof. Shamima Rahman, Great Ormond Street Institute of Child Health, London, United Kingdom. syndrome, whereas others may present with a single clinical feature, genes (responsible for 25–30% of cases) and nuclear genes. Modes of such as an epileptic encephalopathy, leukoencephalopathy, myopathy, inheritance include maternal (for mtDNA variants), autosomal reces- or isolated optic atrophy. sive, X-linked, and de novo dominant. MEGDEL (3-methylglutaconic aciduria with deafness and encephalopathy, Leigh-like) syndrome is LEIGH SYNDROME a subtype of Leigh syndrome caused by biallelic variants in SERAC1 Leigh syndrome, or subacute necrotizing encephalomyelopathy, is a encoding a protein involved in remodeling mitochondrial membrane clinical syndrome of neurodevelopmental delay and/or regression and lipids. Affected infants typically fail the newborn hearing screen and variable other neurologic features, including dystonia, hypotonia, spas- have problems with hypoglycemia and hyperammonemia related to ticity, ataxia, and seizures, with characteristic MRI brain appearances hepatic dysfunction. Some infants succumb to liver failure, but hepatic and biochemical evidence of mitochondrial dysfunction. Peak onset is function improves in most affected individuals, who later progress to usually in the first 2 years of life (mean 7 months), although longer sur- a neurodegenerative course with prominent dystonia and loss of skills. viving cases and adult onset are both recognized. Initial symptoms may A few causes of Leigh syndrome are potentially treatable. %ese be nonneurologic, including feeding di$culties, vomiting, and poor include deficiencies of biotinidase (an enzyme required for biotin weight gain in infancy. Eye involvement is a frequent finding, including recycling within the cell), the thiamine transporter SLC19A3 (also nystagmus, ptosis, PEO, optic atrophy, and retinitis pigmentosa. MRI associated with biotin-thiamine–responsive basal ganglia disease), reveals bilateral, usually symmetric T2-weighted hyperintense lesions and proteins required for biosynthesis of CoQ10, a mobile electron car- variably affecting the basal ganglia, thalamus, midbrain, and brainstem rier in the mitochondrial respiratory chain. All other forms of Leigh structures (Fig. 638.7). %ese imaging lesions re&ect the neuropathol- syndrome have no curative treatments and are associated with a pro- ogy, which consists of spongiform lesions with cavitation, neuronal gressive neurodegenerative course with early death, usually caused by loss, demyelination, and capillary proliferation. respiratory failure secondary to brainstem lesions affecting the respi- Biochemical features are variable in Leigh syndrome and include ratory center. Median age at death was reported as 2.4 years in one elevated lactate in blood and/or cerebrospinal &uid (CSF) and isolated cohort, but this is variable and related to the underlying genetic cause. or combined deficiency of one or more OXPHOS enzymes. Normal Longer survival has been reported in some forms of Leigh syndrome, biochemical findings do not exclude the diagnosis. Leigh syndrome including MEGDEL and deficiencies of SURF1 (an assembly factor is genetically heterogeneous, and more than 100 monogenic causes for OXPHOS complex IV) and SUCLA2 (a subunit of the Krebs cycle have been identified, including variants in both mtDNA-encoded enzyme succinyl-CoA ligase).! ) D 4 4 4 4 4 @ A 0 C @ AE A ( ( E 2E @ C @ @ E. A @ @DA A @@ ( E AF @ C , A@ @ C 4  Chapter 638 ◆ Encephalopathies 3697 NAA NAA Cho Cr Cho Cr Lactate MI MI Lactate B Lactate E NAA NAA Cho Cho Cr Cr Lactate A C D F Fig. 638.7 Complex I deficiency in an 8-yr-old child with magnetic resonance examinations acquired approximately 3 mo apart. Axial T2-weighted (A), short echo magnetic resonance spectroscopy (MRS) (B), and long echo MRS (C) images were obtained. The imaging reveals a pattern char- acteristic of Leigh syndrome with an abnormal hyperintense signal bilaterally within the caudate and globus pallidus. The MRS image acquired in the left basal ganglia at a period of clinical exacerbation caused by febrile illness demonstrates a dramatic elevation of lactate compared with her routinely observed levels as shown in axial T2-weighted (D), short echo MRS (E), and long echo MRS (F) images. The spectra acquired 3 mo later demonstrate a significant reduction in lactate. A comparison of the imaging data is unremarkable between the examinations. The dramatic elevation of lactate revealed on MRS in (B) and (C) corresponds to worsening clinical symptoms (seizures and leg stiffening). The lactate levels observed in (E) and (F) are typical and consistent with this mitochondrial defect. (From Cecil KM. MR spectroscopy of metabolic disorders. Neuroimaging Clin N Am. 2006;16:87–116.) Table 638.7 Mitochondrial DNA Depletion Syndromes GENE* FUNCTION CLINICAL FEATURES mtDNA DEPLETION MULTIPLE DELETIONS POLG mtDNA replication Alpers, juvenile epilepsy + + syndromes, ataxia, PEO TWNK mtDNA replication Hepatocerebral disease, + + IOSCA, juvenile epilepsy syndromes, PEO TFAM mtDNA replication Hepatocerebral disease + MGME1 mtDNA replication Encephalomyopathic + + SLC25A4 Nucleoside metabolism Encephalomyopathic, cardiac + + DGUOK Nucleoside metabolism Hepatocerebral disease + + TK2 Nucleoside metabolism Progressive myopathy + + MPV17 Nucleoside metabolism Hepatocerebral disease + + RRM2B Nucleoside metabolism Encephalomyopathic, SNHL, + + renal tubulopathy SUCLA2 Nucleoside metabolism Encephalomyopathic (LSS), + SNHL SUCLG1 Nucleoside metabolism Encephalomyopathic, + hepatocerebral disease TYMP Nucleoside metabolism MNGIE + + *All are recessive disorders, but, in addition, de novo dominant variants of SLC25A4 may also present as MDDS. IOSCA, Infantile-onset spinocerebellar ataxia; LSS, Leigh syndrome spectrum; MNGIE, mitochondrial neurogastrointestinal encephalopathy; PEO, progressive external ophthalmoplegia. Courtesy Prof. Shamima Rahman, Great Ormond Street Institute of Child Health, London, United Kingdom. MITOCHONDRIAL DNA DEPLETION SYNDROMES Repeated episodes of status epilepticus frequently lead to a median %e most prevalent MDDS is Alpers-Huttenlocher syndrome (pro- age of death of around 16 months (there is typically a median of 4 gressive neuronal degeneration of childhood with epilepsy, PNDE) months between presentation with seizures and death). Sodium val- caused by recessively inherited gene variants in POLG encoding the proate is absolutely contraindicated in Alpers-Huttenlocher syndrome catalytic subunit of DNA polymerase γ, the polymerase responsible for and other presentations of POLG disease because exposure to valproate replicating the mtDNA. Affected individuals frequently present with may trigger fatal hepatic failure. intractable epilepsy, particularly epilepsia partialis continua, around Recessive pathologic variants of at least 12 genes have been linked to 12 months of age. A characteristic EEG finding in the early stages of infantile- and childhood-onset MDDS (Table 638.7). %ere is often a the disease is rhythmic high amplitude with delta spikes (RHADS). period of normal development lasting weeks to months before clinical ) D 4 4 4 4 4 @ A 0 C @ AE A ( ( E 2E @ C @ @ E. A @ @DA A @@ ( E AF @ C , A@ @ C 4 3698 Part XXV ◆ The Nervous System A B C Fig. 638.8 Mitochondrial encephalomyopathy, lactic acidosis, and strokelike symptoms (MELAS) in a 13-yr-old male. Axial diffusion-weighted im- aging (A), axial apparent diffusion coefficient (ADC) map (B), and an axial arterial spin labeling color map (C) are shown. Scattered foci of vasogenic edema denoted by arrows corresponding to increased perfusion are identified in the acute phase of the disease in the right cerebral hemisphere. (From Zuccoli G, Cecil KM. Inherited metabolic and neurogenerative disorders. In: Coley BD, ed. Caffey’s Pediatric Diagnostic Imaging, 13th ed. Philadelphia: Elsevier; 2019: Fig. 33.8, p. 312.) manifestations become apparent. Associated organ involvement may from fatal infantile mitochondrial myopathies, rapid testing for the provide a clue to the underlying genetic diagnosis: sensorineural hear- m.14674T>G/C variants is recommended in all infants presenting with ing loss (SNHL) and methylmalonic aciduria occur in SUCLA2 defects, severe muscle weakness and lactic acidosis, so that ventilatory support SNHL and renal tubular involvement in RRM2B defects, and hepatic can be provided to affected infants if needed. involvement is associated with DGUOK, MPV17, POLG, TWNK, Another form of RIRCD is a reversible hepatopathy caused by reces- TFAM, and SUCLG1 gene variants. Thymidine kinase 2 (TK2) defi- sive variants in the TRMU gene encoding a protein required to modify ciency appears to be a special case because this disorder leads to a pure mitochondrial tRNAs. Affected infants present with acute liver failure, myopathic presentation in most affected cases. Clinical response to variably associated with encephalomyopathic features.! nucleoside supplementation has been reported for TK2 deficiency but not for any other form of MDDS.! KEARNS-SAYRE SYNDROME KSS is defined by a clinical triad of PEO, pigmentary retinopathy, and DISORDERS OF COENZYME Q10 BIOSYNTHESIS heart block, with age of onset G and m.14674T>C. Although all hemianopia during the strokelike episodes, ptosis, optic atrophy, pig- maternally related individuals are homoplasmic for the variant, only mentary retinopathy, SNHL, exercise intolerance, cognitive decline, GI a small proportion are clinically affected. Studies have also identi- dysmotility, cardiomyopathy, renal impairment, and diabetes mellitus. fied potential modifying variants in several nuclear-encoded genes Eighty percent of cases have a common maternally inherited mtDNA involved in mitochondrial translation, particularly EARS2. Spontane- gene variant m.3243A>G in the MT-TL1 gene encoding a tRNA for ous recovery of muscle strength is associated with excellent neurode- leucine. %is gene variant is present in 1 in 400 of the general popu- velopmental outcomes. Because it is not possible to distinguish RIRCD lation, yet MELAS is a rare disorder. Most individuals harboring the ) D 4 4 4 4 4 @ A 0 C @ AE A ( ( E 2E @ C @ @ E. A @ @DA A @@ ( E AF @ C , A@ @ C 4  Chapter 638 ◆ Encephalopathies 3699 m.3243A>G variant are asymptomatic or oligosymptomatic or have focal initially, often affecting the right hand. Later they become gener- non-MELAS presentations, including maternally inherited diabetes alized, including epilepsia partialis continua (EPC), and are refractory and deafness (MIDD), cardiomyopathy, sudden unexpected death, or to therapy. %e ataxia neuropathy spectrum (ANS) is characterized by isolated renal involvement (focal segmental glomerulosclerosis). Other ataxia and neuropathy and includes the previous acronyms MIRAS causes of MELAS include other mtDNA variants, particularly in the (mitochondrial recessive ataxia syndrome) and SANDO (sensory MT-TL1 gene or in mtDNA-encoded subunits of complex I (especially ataxia, neuropathy, dysarthria, ophthalmoplegia). ANS also frequently ND5), and occasionally POLG disease can mimic MELAS.! leads to an encephalopathy with seizures, so there is some overlap between MEMSA and ANS. POLG disease may also mimic MELAS, MYOCLONIC EPILEPSY WITH RAGGED RED FIBERS MERRF, and MNGIE. Variants in the MT-ATP6 gene have also been MERRF is a maternally inherited syndrome characterized by pro- linked to this condition.! gressive myoclonic epilepsy and cerebellar ataxia with nystagmus and dysarthria. Onset may be in late childhood or adult life, and the disor- MITOCHONDRIAL LEUKOENCEPHALOPATHIES der may be rapidly progressive or have a more indolent course. Other Several recessive mitochondrial disorders cause cavitating leukoen- neurologic features include other seizure types, spasticity, peripheral cephalopathies (Table 638.8) that typically present in infancy or early neuropathy, SNHL, ptosis, PEO, optic atrophy, cognitive decline, and childhood with acute- or subacute-onset of motor regression. Other psychiatric manifestations. MERRF can also mimic MELAS, includ- clinical features include epileptic encephalopathy, hemiparesis, spastic ing strokelike episodes. MERRF is typically a multisystemic disorder; paraparesis, bulbar problems, and visual loss (optic atrophy). Mito- extraneurologic features include multiple symmetric lipomatosis, chondrial leukoencephalopathies may also present later in childhood endocrine disturbance (growth hormone deficiency, hypothyroid- or in adult life. Some of the mitochondrial tRNA aminoacyl synthe- ism, adrenal insu$ciency), and cardiomyopathy. A common mtDNA tase deficiencies appear to cause specific white matter changes. Other pathologic variant, m.8344A>G in the MT-TK gene encoding the genetic causes of mitochondrial leukoencephalopathy include variants tRNA for lysine, accounts for 80% of cases of MERRF. Patients with in subunits of complexes I and II and defects of iron-sulfur cluster bio- a very high percentage of this variant (typically >90%) present with synthesis (see Table 638.8).! Leigh syndrome in infancy. %e remaining patients with MERRF have other mtDNA tRNA gene variants; occasionally POLG disease LEBER HEREDITARY OPTIC NEUROPATHY AND may mimic MERRF.! AUTOSOMAL DOMINANT OPTIC ATROPHY Leber hereditary optic neuropathy (LHON) and autosomal dominant NEUROGENIC MUSCLE WEAKNESS, ATAXIA, AND optic atrophy (ADOA) are two mitochondrial optic neuropathies that RETINITIS PIGMENTOSA may occasionally present with additional encephalomyopathic features. NARP is a maternally inherited disorder caused by a relatively com- LHON is maternally inherited and typically presents in the second or mon mtDNA gene variant, m.8993T>G, in the MT-ATP6 gene encod- third decade of life (mean onset ∼20 years, but childhood presenta- ing the ATP6 subunit of ATP synthase (OXPHOS complex V). Patients tion is well-recognized) with subacute or acute visual loss sequentially usually have a gene variant load of ∼70%, but those with a higher vari- affecting both eyes. %ree common mtDNA variants in genes encoding ant load (typically >90%) of the same variant present with maternally complex I subunits (m.3460G>A in MT-ND1, m.11778G>A in MT- inherited Leigh syndrome. Clinical presentation of NARP is usually ND4, and m.14484T>C in MT-ND6) account for 90% of cases. Pen- in late childhood or early adult life with numbness and paresthesias etrance is incomplete, and there is an extreme male preponderance, caused by the sensory neuropathy associated with muscle weakness which may be explained by a protective effect of estrogen in females and ataxia. Retinitis pigmentosa initially causes poor night vision and with LHON variants. In most cases LHON presents as an isolated progresses slowly to severe visual loss. Other clinical features include optic neuropathy, but other clinical manifestations in occasional cases developmental delay, learning disability, dementia, seizures, SNHL, include dystonia (with bilateral striatal necrosis), peripheral neuropa- diabetes mellitus, and cardiac conduction defects. MT-ATP6 variants thy, or cardiac conduction defects. have also been reported to cause axonal Charcot-Marie-Tooth disease ADOA, also known as Kjer disease, is t